The recently emerged framework of optogenetic technology combines optical and genetic tools to use light for controlling the activity of electrically excitable cell in a cell-targeted, cell-autonomous with millisecond temporal resolution (Miesenböck, G., (2009) Science 326, 395-399). Some technologies rely on chemical means through direct targeting of endogenous channels and receptors with caged signaling molecules, such as glutamate that are biologically inert until they become uncaged by the application of a light pulse. (Zemelman et al., (2003) Proc Natl Acad Sci USA 100, 1352-1357; and Ellis-Davies, G. C. R., (2007) Nat Methods 4, 619-628). These reagents do not allow for consecutive stimulation, they have little cellular specificity and force the researcher to target the treated brain regions based on anatomical rather than function considerations. Several groups have pioneered the use of photoisomerizable groups and reverse-engineered ion channels as light-controlled switches for vastly improved specificity and cycling properties (Banghart, M. et al., (2004) Nat Neurosci 7, 1381-1386; and Volgraf, M. et al., (2006) Nat Chem Biol 2, 47-52). While promising, the need for access to chemical expertise has hindered the widespread adoption of these reagents. However, most optogenetic technology takes the form of genetically encoded photoreceptors, microbial opsins such as Channelrhodopsin and Halorhodopsin that conduct or pump ions in a light-dependent manner and can be used without exogenously added chemical. Microbial opsins are not ion selective; they can therefore not be used to modulate a cell's K+ independently from Na+ conductance. They also do not allow the modulation of endogenous channels with analog precision.
Peptide neurotoxins and endogenous neuropeptides work by binding with extraordinarily high affinity and specificity to receptors in animal targets, that most of the time are proteins critical in neuronal signaling and muscle contraction. Because of this high affinity and specificity, peptide toxins have been used to identify and purify various receptors and channels, and are useful in study signaling pathways. Venomous animals produce biomolecule libraries that have evolved to paralyze prey by perturbing ion channel homeostasis. One major constituent of animal venoms are small peptide ligands, which are instrumental in ion channel research and have allowed scientists to probe the function of one of the most complex biological machines, the brain (Olivera, B. M., (1997) Mol Biol Cell 8, 2101-2109; Harvey, A. L., (2001) Toxicon 39, 15-26; Blumenthal, K. M. and Seibert, A. L., (2003) Cell Biochem Biophys 38, 215-238; Corzo, G. and Escoubas, P., (2003) Cell Mol Life Sci 60, 2409-2426; Nirthanan, S., and Gwee, M. C. E., (2004) J. Pharmacol. Sci. 94, 1-17; Terlau, H. and Olivera, B. M., (2004) Physiol Rev 84, 41-68; Koh, D. C. I. et al., (2006) Cell. Mol. Life Sci. 63, 3030-3041; and Kini, R. M. and Doley, R., (2010) Toxicon 56, 855-867). Toxins that target ion channels block either ion conduction through the channel pore or allosterically affect the channel's gating properties; however, their activity cannot be controlled by light.